The invention relates to the use of (+)-tramadol or 0-demethyltramadol, in particular (+)-O-demethyltramadol, O-desmethyl-N-mono-desmethyltramadol, in particular (+)-O-desmethyl-N-mono-desmethyltramadol as free bases and/or in the form of physiologically compatible salts for the production of a pharmaceutical preparation for the treatment of increased urinary urgency or urinary incontinence and to corresponding pharmaceutical preparations and to a method for the treatment of increased urinary urgency or urinary incontinence.
Urinary incontinence is the involuntary release of urine, which occurs in an uncontrolled manner when the pressure within the bladder exceeds the pressure required to seal the ureter. This may be caused, on the one hand, by increased internal bladder pressure (for example due to detrusor instability) resulting in urge incontinence and, on the other hand, by reduced sphincter pressure (for example after giving birth or surgical intervention) resulting in stress incontinence. The detrusor is the coarsely bundled, multilayer bladder wall musculature, contraction of which results in voiding of urine, while the sphincter is the muscle which closes the urethra. Mixed forms of these types of incontinence occur, as do so-called overflow incontinence (for example in cases of benign prostate hyperplasia) or reflex incontinence (for example after spinal cord damage). Further details in this connection may be found in Chutka, D. S. and Takahashi, P. Y., 1998, Drugs 560: 587-595.
Urinary urgency is the state of increased bladder muscle tension directed towards voiding of urine (micturition) as bladder capacity is approached (or exceeded). This tension acts as the micturition stimulus. Increased urinary urgency is taken in particular to mean the occurrence of premature or more frequent, sometimes even painful urinary urgency, going as far as urinary compulsion. This consequently results in distinctly more frequent micturition. Possible causes are bladder inflammation and neurogenic bladder dysfunction as well as vesical tuberculosis. However, not all causes have yet been explained.
Increased urinary urgency and urinary incontinence are extremely unpleasant and those suffering from these symptoms have a clear need to alleviate them for as long as possible.
Increased urinary urgency and in particular urinary incontinence are conventionally treated somatically with substances which are involved in the reflexes of the lower urinary tract (Wein, A. J., 1998, Urology 51 (Suppl. 21): 43-47). These are generally medicines which have an inhibitory action on the detrusor muscle, which is responsible for the pressure within the bladder. These medicines are, for example, parasympatholytics such as oxybutynin, propiverine or tolterodine, tricyclic antidepressants such as imipramine or muscle relaxants such as flavoxate. Other medicines which in particular increase the strength of the urethra or the neck of the bladder exhibit an affinity to xcex1-adrenergic receptors such as ephedrine, to xcex2-adrenergic receptors such as clenbuterol or are hormones such as oestradiol. Certain opioids, diarylmethylpiperazines and diarylmethylpiperidines are also described for this indication in WO 93/15062.
WO 98/46216 demonstrated for the first time that tramadol may also be used for the indications of increased urinary urgency and urinary incontinence. Tramadol ((1RS,2RS)-2-dimethylaminomethyl-1-(3-methoxyphenyl)cyclohexanol) is a racemate and a known centrally acting analgesic, which strongly inhibits pain without causing the side effects known for opioids (J. Pharmacol. Exptl. Ther. 267, 331 (1993)).
It must, however, be born in mind that, for the indications under consideration, drug therapy will generally be of very long duration and, unlike many situations in which analgesics are used, the affected individuals feel themselves to be in a very unpleasant, but not intolerable situation. Care must accordingly be taken in this case, still more than with analgesics, to avoid side effectsxe2x80x94the affected individuals will not want to swap one evil for another.
Although tramadol exhibits much fewer side effects than opioids, the use of tramadol is associated with a few, sometimes unpleasant, dose-related side effects. Moreover, analgesic action is largely undesirable in the long-term treatment of urinary incontinence. Using tramadol racemate for this indication thus has disadvantages because, even though the racemate has an effect on bladder function even at relatively low doses, therapeutic dosages may cause unwanted side effects, especially in certain groups of patients.
The object of the present invention was accordingly to identify substances which are helpful in the treatment of increased urinary urgency or urinary incontinence and which preferably simultaneously exhibit reduced side effects and less analgesic action than known from the prior art.
It has surprisingly now been found that (+)-tramadol possesses excellent effect on bladder function and is accordingly suitable for the treatment of such conditions and exhibits this action at considerably lower dosages than the racemate.
The present invention accordingly provides the use of (+)-tramadol as a free base and/or in the form of physiologically compatible salts for the production of a pharmaceutical preparation for the treatment of increased urinary urgency or urinary incontinence.
Tramadol is a racemate and consists of equal quantities of (+)- and (xe2x88x92)-enantiomers. It is known from analgesic use that the enantiomers of tramadol have a differing pharmaceutical profile from the racemate. The (+)-enantiomer is distinguished by an opiate-like analgesic action, which is stronger than that of tramadol, while distinct inhibition of noradrenaline reuptake is observed with the (xe2x88x92)-enantiomer. It has been proven for (+)- and (xe2x88x92)-tramadol that, depending upon the model, the two enantiomers mutually reinforce their action (Raffa, R. et al., 1993, J. Pharmacol. Exptl. Ther. 267:331). It is obvious to assume that the potent analgesic action of tramadol is based on this mutually dependent reinforcement of action.
Completely at variance with this experience from analgesic use, investigation of the separate enantiomers with regard to their effect on bladder function revealed a surprisingly different picture. (+)-Tramadol was not only distinctly more active than the racemate, but was even considerably more active than twice the dose of the racemate mixture of (+)- and (xe2x88x92)-tramadol used. It may, however, be concluded from this not only that (+)-tramadol is the actual active substance, but also that (xe2x88x92)-tramadol appears not only to be inactive but, in contrast with analgesic use in the racemate, even appears to inhibit the action of (+)-tramadol on bladder function.
Using (+)-tramadol thus has clear advantages over the prior art, namely using tramadol as a racemate (WO 98/46216), as it is possible to use considerably lower dosages of distinctly less than 50% of the dosage required for tramadol. Side effects are correspondingly reduced as (xe2x88x92)-tramadol also makes a contribution to these, in particular also to the analgesic action. Possible methods for producing (+)-tramadol are described in Arzneim. -Forsch./Drug Res. 28 (I), 114 (1978) and in particular preferably in DE 196 01 745 C1.
When using (+)-tramadol, it is not necessary, but is preferred, to use solely the (+)-tramadol enantiomer. A smaller proportion of (xe2x88x92)-tramadol relative to the (+)-tramadol is, however, acceptable, and may be contained in the use according to the invention.
Suitable salts for the purpose of this invention and in each of the claimed uses are salts of the particular active substance with inorganic or organic acids and/or a sugar substitute such as saccharin, cyclamate or acesulfame. The hydrochloride is, however, particularly preferred.
The present invention also provides the use of O-demethyltramadol and/or its enantiomers, diastereomers, bases or salts of physiologically compatible acids for the production of a pharmaceutical preparation for the treatment of increased urinary urgency or urinary incontinence. It is in particular preferred to use (+)-O-demethyltramadol as a free base and/or in the form of physiologically compatible salts. In vivo, tramadol forms the metabolite O-demethyltramadol, which is likewise present as an enantiomer mixture. With regard to analgesic action, investigations have revealed that both the two tramadol enantiomers and the two enantiomers of the tramadol metabolites are involved in the analgesic action (J. Pharmacol. Exptl. Ther. 260, 275 (1992); Arzneim. Forschung 38, 877 (1988)).
Surprisingly, the racemate (O)-demethyltramadol also had a clear effect on bladder function even at low concentrations. More thorough investigation of the enantiomers revealed that (+)-O-demethyltramadol was apparently responsible for the entire effect on bladder function. EP 534 628 and WO 93/04675 disclose the production of O-demethyltramadol as a racemate or in enantiomer form. The (+)-O-demethyltramadol enantiomer is preferably produced using the process described in DE 196 01 744 C2.
When using (+)-O-demethyltramadol, it is not necessary, but is preferred, to use solely the (+)-O-demethyltramadol enantiomer. A smaller proportion of (xe2x88x92)-O-demethyltramadol relative to the (+)-O-demethyltramadol is, however, acceptable, and may be contained in the use according to the invention.
The present invention also provides the use of O-desmethyl-N-mono-desmethyltramadol and/or its enantiomers, in particular mixtures of its enantiomers or of a single enantiomer, diastereomers, bases or salts of physiologically compatible acids for the production of a pharmaceutical preparation for the treatment of increased urinary urgency or urinary incontinence. It is in particular preferred to use (+)-O-desmethyl-N-mono-desmethyltramadol as a free base and/or in the form of physiologically compatible salts.
O-desmethyl-N-mono-desmethyltramadol (referred to as M5 in some places in the following text and in the literature) is known as one of the in vivo metabolites of tramadol (1RS, 2RS)-2[(dimethylamino)methyl]-1-(3-methoxyphenyl) cyclohexanol (Lintz et al., Arzneim.- Forsch./Drug Res. 31(11), 1932-1943, 1981). M5 penetrates the blood-brain barrier to only a limited extent, as the effects on the central nervous system, for example analgesic effects, are distinctly less pronounced on intravenous administration than on intracerebroventricular administration. Surprisingly, the racemate O-demethyltramadol also had a clear effect on bladder function even at low concentrations. More thorough investigation of the enantiomers revealed that (+)-O-desmethyl-N-mono-desmethyltramadol was apparently responsible for the entire effect on bladder function.
When using (+)-O-desmethyl-N-mono-desmethyltramadol, it is not necessary, but is preferred, to use solely the (+)-O-desmethyl-N-mono-desmethyltramadol enantiomer. A smaller proportion of (xe2x88x92)-O-desmethyl-N-mono-desmethyltramadol relative to the (+)-O-desmethyl-N-mono-desmethyltramadol is, however, acceptable, and may be contained in the use according to the invention.
Although the compounds according to the invention exhibit only slight side effects, it may be advantageous, for example to avoid certain types of dependency, also to use morphine antagonists, in particular naloxone, naltrexone and/or levallorphan, in addition to (+)-tramadol, O-demethyltramadol or (+)-O-demethyltramadol, O-desmethyl-N-mono-desmethyltramadol or (+)-O-desmethyl-N-mono-desmethyltramadol.
The invention furthermore relates to pharmaceutical preparations for the treatment of increased urinary urgency or urinary incontinence, which preparations contain as active substance at least (+)-tramadol as a free base and/or in the form of physiologically compatible salts optionally together with additives and/or auxiliary substances or pharmaceutically acceptable excipients. In the corresponding pharmaceutical preparations it is not necessary, but is preferred, to use solely the (+)-tramadol enantiomer. A smaller proportion of (xe2x88x92)-tramadol relative to the (+)-tramadol is, however, acceptable, and may be contained in the pharmaceutical preparations according to the invention.
The invention also comprises pharmaceutical preparations for the treatment of increased urinary urgency or urinary incontinence, which preparations contain O-demethyltramadol and/or its enantiomers, diastereomers, bases or salts of physiologically compatible acids, in particular (+)-O-demethyltramadol as a free base and/or in the form of physiologically compatible salts optionally together with additives and/or auxiliary substances or pharmaceutically acceptable excipients. In the corresponding pharmaceutical preparations containing (+)-O-demethyltramadol, it is not necessary, but is preferred, to use solely the (+)-O-demethyltramadol enantiomer. A smaller proportion of (xe2x88x92)-O-demethyltramadol relative to (+)-O-demethyltramadol is, however, acceptable, and may be contained in the pharmaceutical preparations according to the invention.
The invention also comprises pharmaceutical preparations for the treatment of increased urinary urgency or urinary incontinence, which preparations contain as active substance at least O-desmethyl-N-mono-desmethyltramadol and/or its enantiomers, in particular mixtures of its enantiomers or a single enantiomer, diastereomers, bases or salts of physiologically compatible acids, in particular (+)-O-desmethyl-N-mono-desmethyltramadol as free base and/or in the form of physiologically compatible salts optionally together with additives and/or auxiliary substances. In the corresponding pharmaceutical preparations containing (+)-O-desmethyl-N-mono-desmethyltramadol, it is not necessary, but is preferred, to use solely the (+)-O-desmethyl-N-mono-desmethyltramadol enantiomer. A smaller proportion of (xe2x88x92)-O-desmethyl-N-mono-desmethyltramadol relative to the (+)-O-desmethyl-N-mono-desmethyltramadol is, however, acceptable, and may be contained in the pharmaceutical preparations according to the invention.
Suitable salts for the purposes of this invention and in each of the claimed uses are salts of the particular active substance with inorganic or organic acids and/or a sugar substitute such as saccharin, cyclamate or acesulfame. The hydrochloride is, however, particularly preferred.
Suitable additives and/or auxiliary substances for the purposes of this invention are any substances known to the person skilled in the art of obtaining pharmaceutical formulations. Selection of these auxiliary substances and the quantities thereof to be used depend upon whether the pharmaceutical preparation is to be administered orally, intravenously, intraperitoneally, intradermally, intramuscularly, intranasally, buccally or locally. Preparations in the form of tablets, chewable tablets, coated pills, capsules, granules, drops, elixirs or syrups are suitable for oral administration, while solutions, suspensions, readily reconstitutible dry preparations and sprays are suitable for parenteral, topical and inhalatory administration. Suppositories for rectal administration are another possibility. Examples of suitable percutaneous administration forms are use in a reservoir in dissolved form, in a carrier film or a plaster, optionally with added agents which promote skin penetration. Examples of auxiliary substances and additives for oral administration forms are suspending agents, lubricants, binders, fillers, mould release agents, optionally solvents, flavourings, sugar, in particular excipients, diluents, colorants, antioxidants etc. Waxes or fatty acid esters may, inter alia, be used for suppositories, while excipients, preservatives, suspending auxiliaries etc. may be used for parenteral administration forms. The quantities of active substance to be administered to patients vary as a function of patient weight, the route of administration and the severity of the condition. The compounds according to the invention may be released in a delayed manner from oral, rectal or percutaneous formulations. Such delayed release formulations, in particular in the form of a xe2x80x9conce dailyxe2x80x9d preparation, which need be taken only once per day, are particularly preferred for the indication according to the invention.
Pharmaceutical preparations containing at least 0.05 to 90.0% of the active substance, in particular low active doses, are also preferred in order to avoid side effects or analgesic action.
Although the pharmaceutical preparations according to the invention exhibit only slight side effects, it may be advantageous, for example to avoid certain types of dependency, also to use morphine antagonists, in particular naloxone, naltrexone and/or levallorphan, in addition to (+)-tramadol, O-demethyltramadol or (+)-O-demethyltramadol, O-desmethyl-N-mono-desmethyltramadol or (+)-O-desmethyl-N-mono-desmethyltramadol.
The invention furthermore also relates to a process for the treatment of increased urinary urgency or urinary incontinence, in which process (+)-tramadol is used as a free base and/or in the form of physiologically compatible salts or corresponding processes in which O-demethyltramadol and/or its enantiomers, diastereomers, bases or salts of physiologically compatible acids, in particular (+)-O-demethyltramadol are/is used as a free base and/or in the form of physiologically compatible salts. A corresponding process, in which O-desmethyl-N-mono-desmethyltramadol and/or its enantiomers, diastereomers, bases or salts of physiologically compatible acids, in particular (+)-O-desmethyl-N-mono-desmethyltramadol is/are used as free base and/or in the form of physiologically compatible salts, is also encompassed by the invention.